Estrogen receptor (ER) signaling is required for the growth of a majority of breast and endometrial tumors. Ligands of the aryl hydrocarbon receptor (AHR) can interfere with the action of estrogens, which has led to proposals that these compounds could be developed as therapies for ER-dependent cancers. However, AHR ligands also can produce estrogenic responses in the absence of ER ligands. A large number of environmental contaminants (including combustion products, "dioxins" and polychlorinated biphenyls), plant natural products, and therapeutic compounds interact with AHR. However, these compounds differ in their abilities to activate AHR, and it is unclear which may promote or interfere with ER signaling. Both ER and AHR act primarily as regulators of gene transcription, but how AHR participates in ER-mediated regulation is not clear. The overall objective of this project is to determine the extent and mechanism(s) of cross-talk between ER and AHR. This research seeks to connect molecular mechanisms of AHR and ER action to expression of target genes and ultimately to cell proliferation. Our hypothesis is that this cross-talk will depend on the specific ligands of each receptor present, the tissue type, and the response being measured. [unreadable] Following treatment of breast and endometrial cancer cells with various combinations of AHR and ER ligands, we will use quantitative RT-PCR to measure expression of their target genes. Regulation of specific genes will be explored further by following recruitment of AHR, ER, and transcriptional cofactors to regulatory sequences by chromatin immunoprecipitation. Finally, these molecular results will be connected to the endpoint of medical interest, tumor cell proliferation. Changes in proliferative status will be linked to expression of target genes that regulate the cell cycle. These studies will build a mechanistic understanding of the mechanisms by which AHR interacts with ER signaling, and thereby provide a clearer picture of the potential for AHR ligands to inhibit or promote the growth of estrogen-dependent tumors. [unreadable] [unreadable] [unreadable]